Genetic Testing For BRCA1 Mutations Research Articles

Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ.

1512 Background: The frequency of a BRCA mutation among women with ductal carcinoma in situ (DCIS) has not been well described. Consequently, patients with DCIS were not historically considered ideal candidates for genetic testing even in the presence of a family history of breast and ovarian cancer. Therefore, we examined the prevalence of BRCA1/2 mutations in women diagnosed with DCIS. Methods: Patients with DCIS, who were referred for genetic counseling and underwent genetic testing, were included in the study. Patient characteristics were obtained from a prospectively maintained research database. This study was approved by institutional review board. The likelihood of carrying a BRCA mutation was calculated using the BRCAPRO model (Version 5.1). Chi-square analysis was used to determine the difference among mutations carriers vs. non-carriers with DCIS. Results: One hundred and twenty nine patients diagnosed with DCIS underwent genetic testing for BRCA mutations. Twenty-eight percent (37/129) of DCIS patients tested positive for a deleterious BRCA mutation (15 BRCA1, and 22 BRCA2). In addition, 6 were found to have a variant of uncertain significance (VUS). The average age of diagnosis was 46.2 yrs (30-69) in BRCA positive patients and 43.5 yrs (26-65) in BRCA negative patients (p =0.177). Patients who tested positive for the BRCA mutations had significantly more family history of breast and ovarian cancer (p=0.021, p=0.006 (respectively) than those who tested negative; as reflected by the BRCAPro calculation (p ≤0.0001). Fifty seven percent of BRCA positive patients had one breast removed for prophylactic reasons while only 28% BRCA negative patients did (p=0.004). This effect was significantly stronger for patients ≤40 (p=0.007). Conclusions: Patients with DCIS and a family history of breast and/or ovarian cancer have a high rate of BRCA positivity regardless of age. These findings suggest that patients with DCIS are appropriate candidates for genetic testing in the presence of family history and regardless of age even if they do not have invasive cancer.

Genetic Testing for BRCA Mutations Can Save Lives

JAMA Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality Susan M. Domchek, MD; Tara M. Friebel, MPH; Christian F. Singer, MD, MPH; D. Gareth Evans, MD; Henry T. Lynch, MD; Claudine Isaacs, MD; Judy E. Garber, MD, MPH; Susan L. Neuhausen, PhD; Ellen Matloff, MS; Rosalind Eeles, PhD; Gabriella Pichert, MD; Laura Van t’veer, PhD; Nadine Tung, MD; Jeffrey N. Weitzel, MD; Fergus J. Couch, PhD; Wendy S. Rubinstein, MD, PhD; Patricia A. Ganz, MD; Mary B. Daly, MD, PhD; Olufunmilayo I. Olopade, MD; Gail Tomlinson, MD, PhD; Joellen Schildkraut, PhD; Joanne L. Blum, MD, PhD; Timothy R. Rebbeck, PhD Context: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. Objective: To estimate risk and mortality reduction stratified by mutation and prior cancer status. Design, Setting, and Participants: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. Main Outcomes Measures: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. Results: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). Conclusions: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. doi:10.1001/jama.2010.1237.

Safety and Efficacy of Perforator Flap Breast Reconstruction With Combined Intraabdominal Procedures

Genetic testing for BRCA mutations has led to greater needs for breast reconstruction and prophylactic gynecologic procedures. A retrospective review of all perforator flap breast reconstructions was performed over 5 years. A total of 316 flaps were performed on 232 patients. Nineteen patients had an intraabdominal procedure at the time of their breast reconstruction, including 8 unilateral and 11 bilateral reconstructions (22 flaps). The concomitant procedures incurred an additional mean operative time of 61 minutes. One arterial thrombosis occurred leading to a single flap failure (1/30, 3.3%). No significant differences were noted in complication rates between the combined group and those who did not have a simultaneous procedure (anastomotic complications 3.3% vs. 7.7%; failure rate 3.3% vs. 3.1%; abdominal wound 10.5% vs. 15%; fat necrosis 10% vs. 12.2%). The coordinated effort allowing simultaneous intraabdominal procedures and perforator flap breast reconstruction affords effective reconstruction for those requiring additional procedures without an increase in postoperative complication rates.

Clinical and Pathologic Differences Between BRCA1‐, BRCA2‐, and Non‐BRCA‐Associated Breast Cancers in a Multiracial Developing Country

Mutations in BRCA1 and BRCA2 confer an increased risk to breast and other cancers, but to date there have only been limited numbers of studies of BRCA1- and BRCA2-associated cancers among Asians. Malaysia is a multiracial country with three main races: Malays, Chinese, Indians. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations in this Asian population. We conducted a retrospective review of the medical records of 152 women with breast cancer who underwent genetic testing for BRCA mutations. The patients self-reported ethnicity, age at onset, and clinical stage at diagnosis and tumor pathology were reviewed. A total of 31 patients carried germline deleterious mutations (16 BRCA1, 15 BRCA2). We found that tumors in BRCA1 carriers were more likely to be estrogen receptor (ER)-negative and progesterone receptor (PR)-negative. HER2 was more likely to be negative in both BRCA1 and BRCA2 subjects compared with non-BRCA subjects. We found a strong association between triple-negative status and BRCA1 carriers. In addition, tumors in BRCA1 carriers were more likely to be higher grade than those in BRCA2 and non-BRCA carriers; but the difference was not statistically significant. These results suggest that tumors associated with BRCA1 mutations are distinct from those of BRCA2-associated and non-BRCA-associated breast cancers, and that the tumors associated with BRCA2 mutations are similar to the non-BRCA-associated breast cancers. Further studies are required to determine if the prognosis is different in each of these groups and the best management strategy for each group.

Risk Information Exposure and Direct-to-Consumer Genetic Testing for BRCA Mutations among Women with a Personal or Family History of Breast or Ovarian Cancer

Direct-to-consumer (DTC) BRCA testing may expand access to genetic testing and enhance cancer prevention efforts. It is not known, however, if current DTC websites provide adequate risk information for informed medical decision making. A total of 284 women with a personal or family history of breast/ovarian cancer were randomly assigned to view a "mock" DTC commercial website [control condition (CC); n = 93] or the same "mock" website that included information on the potential risks of obtaining genetic testing online. Risk information was framed two ways: risk information attributed to expert sources (ES; n = 98) and unattributed risk information (URI; n = 93). Participants completed an online survey. End points were intentions to get BRCA testing, testing site preference, and beliefs about DTC BRCA testing. The sample was 82% white, had a mean age of 39 years (range, 18-70 years) and had a mean education of 3 years of college. Women exposed to risk information had lower intentions to get BRCA testing than women in the CC [adjusted odds ratio (OR), 0.48; 95% confidence interval (95% CI) 0.26-0.87; P = 0.016], and less positive beliefs about online BRCA testing (adjusted OR, 0.48; 95% CI, 0.27-0.86; P = 0.014). Women in the ES condition were more likely to prefer clinic-based testing than were women in the CC (adjusted OR, 2.05; 95% CI, 1.07-3.90; P = 0.030). Exposing women to information on the potential risks of online BRCA testing altered their intentions, beliefs, and preferences for BRCA testing. Policy makers may want to consider the content and framing of risk information on DTC websites as they formulate regulation for this rapidly growing industry.

Clinical and Pathologic Characteristics of Patients With BRCA-Positive and BRCA-Negative Breast Cancer

Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations. Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status. Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01). These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non-triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.

Genetic Testing in Diverse Populations

ORE THAN 10 YEARS AFTER BRCA1 AND BRCA2 werediscoveredasmajorbreastcancersusceptibility genes, the medical community is just beginningtogetaglimpseofhowgermlinemutations in these genes might be distributed among racial/ethnic minority populations in the United States. While a growing body of evidence documents the benefits of preventive measureshavingminimalriskforwomenwithidentifiableBRCA1 andBRCA2mutations,genetictestingservicesremainunderutilized by minority women. In this issue of JAMA, John and colleagues 1 provide information regarding the prevalence of pathogenic BRCA1 mutations in a population-based study among5USracial/ethnicgroupsinNorthernCalifornia.PrevalencewasparticularlyhighamongyoungAfricanAmericans, a group that has long been recognized as having a disproportionate burden of aggressive young-onset breast cancer. With more than 200000 women estimated to be diagnosed with breast cancer and more than 40000 deaths from the disease each year, 2 a renewed emphasis on prevention for control of breast cancer is warranted. Women with germline mutations in BRCA1 and BRCA2 genes face dramatically increased risks of breast and ovarian cancers. The decision to pursue genetic testing for BRCA1 and BRCA2, with its associated costs, depends on 2 prerequisites: valid mutation detection methods for the test and effective cancer prevention strategies for mutation carriers. Regarding the first prerequisite, the specificity of genetic testing for BRCA mutations is believed to be 100% and sensitivity is estimated at 85%, 3 although recent studies have shown that analysis of genomic rearrangements,whichwasnotperformedintheUnitedStates until2006,maysignificantlyincreasesensitivity. 4,5 Forthesecond prerequisite, mutation carriers now have the option of choosingfromaspectrumofevidence-basedpreventionstrategies,includingintensivebreastcancersurveillanceusingmag

Association between clinical characteristics and risk‐reduction interventions in women who underwent BRCA1 and BRCA2 testing

Women who are at increased risk for breast and ovarian cancers, especially BRCA1 and BRCA2 mutation carriers, face a myriad of risk-reduction options, including increased surveillance, chemoprevention, prophylactic oophorectomy, and prophylactic mastectomy. However, little is known about which clinical, demographic, or cancer-related factors are associated with risk-reduction interventions. The authors conducted a retrospective review of records for 554 women who had undergone testing at The University of Texas M. D. Anderson Cancer Center between 2000 and 2006 for deleterious BRCA1 and BRCA2 gene mutations. Data were collected on the risk-reduction interventions these women adopted after they underwent genetic testing. These data were tested for associations with demographic and clinical characteristics. Among the 554 women who underwent genetic testing for BRCA mutation, 78 were found to have a deleterious mutation in the BRCA1 gene, and 54 had a mutation in the BRCA 2 gene. Of the 554 women, 85 underwent prophylactic mastectomy, 30 prophylactic oophorectomy, and 52 both surgeries; 387 women opted for surveillance. Women who had BRCA mutations, a history of breast cancer or ductal carcinoma in situ (DCIS), or previous breast biopsies were more likely to have prophylactic surgery. Women with a family history of ovarian cancer were more likely to undergo prophylactic oophorectomy. Women with a personal history of ovarian cancer or advanced breast cancer were more likely to undergo surveillance only. Women with breast cancer who had had a total mastectomy as part of their prior breast cancer treatment underwent prophylactic mastectomy more frequently than women who either had breast-conserving surgery or no history of breast cancer. In multivariate analysis, only positive BRCA mutation carrier status was associated with having had prophylactic surgery. In addition, breast cancer history was significantly associated with prophylactic mastectomy. Women who were BRCA carriers, women who had a history of breast cancer, DCIS, or breast biopsy, or had a family history of ovarian cancer were more likely to have undergone surgery for cancer risk reduction. Women with ovarian cancer or advanced breast cancer were more likely to have undergone surveillance.

Family issues in a psychoeducation group for women with a BRCA mutation

Few services exist for women who test positive for BRCA1 and BRCA2 mutations despite the distress that they and their families may experience. We present one model of a time-limited family-oriented psychoeducation group to provide information and support for nine women who received positive test results. We report on five family-oriented themes that arose from the discussions: distress about possible transmission to children; family conflict about testing; concerns about disclosure; different coping styles and decision making; and underlying family conflict and unresolved grief. We also include recommendations from these women to enhance the services available to families by expanding assessment, and providing written literature and contact information. In addition, referrals for a psychoeducation group, community support group, or psychotherapy may be useful for individuals, couples and families who are considering genetic testing for BRCA mutations.

Qualitative Evaluation of Medical Information Processing Needs of 60 Women Choosing Ovarian Cancer Surveillance or Prophylactic Oophorectomy.

Thirty women who had prophylactic oophorectomy (PO) and thirty women undergoing ovarian cancer surveillance (OCS) completed a one-time in-depth telephone interview exploring information gathering and decision-making processes. There were close similarities between groups, including age, race, marital status, education, menopausal status, number undergoing genetic testing for BRCA mutations, and number of prophylactic mastectomies. The majority of participants indicated overall satisfaction with their final decision. However, many described the information gathering process as frustrating and anxiety provoking. Participants in both groups expressed a need to process medical information within the context of individual psychosocial needs and personal perceptions and experiences. There were recurrent themes with regard to informational and psychosocial needs and personal perceptions and experiences that impacted decision-making process for these women. The present paper is a companion paper to Swisher et al. (J Repr Med 2001, 46:87-94) with the focus of this paper to illustrate the medical informational processing needs identified by this group of women.

A highly sensitive, fast, and economical technique for mutation analysis in hereditary breast and ovarian cancers.

Mutation analysis of complex genes without hotspots for sequence variations, such as BRCA1, is time-consuming and expensive. Of all currently available methods, direct sequencing has the highest sensitivity, but also the highest costs. Other techniques, such as SSCP, DGGE, and PTT, are more economical but, depending on the experience of the investigator, have at best a sensitivity of 90%. We investigated in a prospective study the feasibility and accuracy of the DHPLC technique. We present the application of the DHPLC protocol for BRCA1 mutation detection on a HPLC device from Bio-Tek Kontron Instruments (Neufahrn, Germany). DNA from 46 women with hereditary breast and ovarian cancer undergoing genetic testing for BRCA1 mutations were tested. Of 1,518 amplicons analyzed by DHPLC, corresponding to 33 fragments spanning the entire BRCA1 gene, 626 were also directly sequenced. The comparison demonstrated that DHPLC detected all alterations found by direct sequencing. No false-positive signals were seen in cases of homozygous sequences. Further, no false-negative results were ever obtained in women with mutations or polymorphisms, or both. In cases of known genetic variations, the nature of the alterations could be predicted by DHPLC. We also compared different separation matrices. Up to about 500 injections, no significant differences in sensitivity could be observed between poly(styrene divinylbenzene) and end-capped silica based columns. However, after more than 500 injections, the resolution of hetero- from homoduplex deteriorated rapidly on silica columns.

A highly sensitive, fast, and economical technique for mutation analysis in hereditary breast and ovarian cancers

Mutation analysis of complex genes without hotspots for sequence variations, such as BRCA1, is time-consuming and expensive. Of all currently available methods, direct sequencing has the highest sensitivity, but also the highest costs. Other techniques, such as SSCP, DGGE, and PTT, are more economical but, depending on the experience of the investigator, have at best a sensitivity of 90%. We investigated in a prospective study the feasibility and accuracy of the DHPLC technique. We present the application of the DHPLC protocol for BRCA1 mutation detection on a HPLC device from Bio-Tek Kontron Instruments (Neufahrn, Germany). DNA from 46 women with hereditary breast and ovarian cancer undergoing genetic testing for BRCA1 mutations were tested. Of 1,518 amplicons analyzed by DHPLC, corresponding to 33 fragments spanning the entire BRCA1 gene, 626 were also directly sequenced. The comparison demonstrated that DHPLC detected all alterations found by direct sequencing. No false-positive signals were seen in cases of homozygous sequences. Further, no false-negative results were ever obtained in women with mutations or polymorphisms, or both. In cases of known genetic variations, the nature of the alterations could be predicted by DHPLC. We also compared different separation matrices. Up to about 500 injections, no significant differences in sensitivity could be observed between poly(styrene divinylbenzene) and end-capped silica based columns. However, after more than 500 injections, the resolution of hetero- from homoduplex deteriorated rapidly on silica columns. Hum Mutat 14:333–339, 1999. © 1999 Wiley-Liss, Inc.

A model protocol for evaluating the behavioral and psychosocial effects of BRCA1 testing.

Breast cancer is the most common cancer in American women. A heritable component to breast cancer has been suspected for over a century because of the observation that a woman is at higher risk if she has had one or more first-degree relatives with breast cancer (1). Recent advances in molecular genetics have led to the isolation of a gene called BRCA1 on the long arm of chromosome 17. Mutations in this gene substantially increase the risk in women for breast and ovarian cancers (2,3). Cancer susceptibility conferred by BRCA1 mutations is inherited in an autosomal dominant fashion. A study conducted by the Breast Cancer Linkage Consortium (BCLC) estimated that 45% of the families with a high risk of breast cancer alone and the large majority of breast cancer families who also have at least one individual with ovarian cancer are linked to the 17q site. In the analysis of 214 families collected worldwide through the BCLC, the cumulative risk for breast or ovarian cancer in mutation carriers was estimated to be 59% by age 50 years and 82% by age 70 years (4). Preliminary evidence suggests that there also may be an increased risk of prostate and colon cancers in BRCA1 mutation carriers (5). The penetrance of the gene for both breast and ovarian cancers may vary between families, perhaps due to different functional mutations within the BRCA1 gene (6). In families without a strong history of breast or ovarian cancer, cases are less likely to be associated with this gene. It has been estimated that approximately 5%-10% of the cases of breast cancer in the general population are associated with BRCA1 mutations (7). Germline BRCA1 mutations have been documented in approximately 10% of the women in the general population diagnosed with breast cancer before the age of 35 years (8) and in 13% of the women with breast cancer younger than age 30 years (9). Although the proportion of breast cancer cases associated with BRCA1 mutations is relatively low in the general population, the prevalence of these cancers means that a large number of cases per year are associated with this gene. To date, screening for BRCA1 mutations in the general population has been inhibited by the large number of mutations identified in this gene. However, the recent report of a single BRCA1 mutation in as many as 1% of Ashkenazi Jews raises the possibility of screening in this population in the near future (10). Germline BRCA1 mutations have been documented in eight (21%) of 39 Jewish women with breast cancer before the age of 40 years (9). Testing for mutations in the BRCA1 gene may be the first widespread use of presymptomatic genetic testing introduced into general medical practice (11). Genetic testing for BRCA1 mutations will help at-risk women only if the risk information is beneficial psychologically or if it is translated into effective cancer prevention or surveillance behaviors. However, potential harm may result to those tested if they experience psychological distress, stigmatization, and/or discrimination on the basis of their genetic status (12-14). Previous studies (15-17 )o f cancer screening have provided evidence of adverse psychological reactions to risk information involving distress and impairment in daily functioning. This distress has important consequences for surveillance and prevention. Anxiety has been associated with a reduced likelihood of adherence to mammography, clinical breast examination, and breast selfexamination in both normal and high-risk populations (1820). Cases of genetic discrimination have also been cited (21). These risks are a particular concern, since the medical benefits of genetic testing for cancer susceptibility have yet to be demonstrated. While this new genetic technology provides an unprecedented opportunity for targeted cancer prevention and surveillance efforts, our current knowledge of the behavioral, psychological, and social impacts of this information is too limited to enable the development of protocols that we know will be safe and effective